A systematic review on the efficacy and safety of Infliximab in patients with psoriasis

ABSTRACT

Objective: To assess the efficacy and safety of infliximab for the treatment of psoriasis in a meta-analysis framework.

Methods: Data were extracted by searching the EMBASE (1974–2014), PubMed(1966–2014) and the Cochrane library2013.4^th databases. Only randomized and placebo-controlled studies were selected in this study.

Results: Statistically significant differences in efficacy were found for the infliximab (3 or 5 mg/kg) group compared with the control group which received placebo in the treatment of psoriasis vulgaris [OR 13.55, 95%CI (11.14,16.48)]or[OR85.45, 95%CI (39.13,186.58)]. There were also significant differences in efficacy between the infliximab (5 mg/kg) group and the placebo control group during treatment of psoriasis arthritis (PsA) [OR8.36, 95%CI (5.63, 12.40)]. A controlled trial used infliximab (5 mg/kg) in the treatment of palmoplantar psoriasis. This study showed that the effective rate of the infliximab group was 33.3% (4/12) when compared to the placebo control group, which was 8.3% (1/12).

Conclusion: Infliximab is significantly associated with symptom relief, skin lesion improvement, and an increase in the quality of life of psoriasis patients. The most common drug-induced adverse events were pain, hepatic dysfunction, and infusion reaction.

Keywords:

• Infliximab
• psoriasis
• systematic review
• meta-analysis

Psoriasis is a common chronic skin disease. This disease is characterized by excessive and rapid growth of the epidermal layer of the skin.¹ T lymphocytes are thought to play a vital role in the pathogenesis of psoriasis. Previous reports have shown that the psoriatic T cells are activated memory skin-homing T cells which induce the characteristic disease features via cytokine production.² The most recent studies on the mechanisms involved in the establishment of psoriasis have shown that phenotypic and functional changes of T lymphocytes can cause proliferation and abnormal differentiation of epidermal keratinocytes to induce psoriasis.^3,4 TNF – α can induce T cells to express VEGF mRNA (Vascular Endothelial Growth Factor).⁵ VEGF is a secreted protein produced by cells that stimulates vasculogenesis and angiogenesis.⁶ It is highly associated with psoriatic plaque formation, telangiectasia, and capillary twist of the dermal papilla layer.⁷ TNF-α is produced early on during the induction of inflammation and is involved in the regulation of immune cells. It was found that primarily CD4⁺ T cells, along with some CD8⁺ T cells, secreted TNF-α and TNF-2α when T cells were isolated from psoriatic lesions and analyzed by flow cytometry.^8,9 Infliximab is a chimeric human-murine anti-TNF-α monoclonal antibody, which has been approved for the treatment of rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn's disease, and intractable retinal uveitis in Behcet's disease. Infliximab inhibits or prevents the effective binding of TNF-α with its receptors. Theoretically, it could be approved for the treatment of various types of psoriasis. Our study will analyze the applications of randomized and controlled clinical trials of infliximab in the treatment of psoriasis by meta-analysis in order to evaluate the efficacy and safety of infliximab for the treatment of psoriasis.

Materials and Methods

Inclusion and exclusion criteria

Inclusion criteria

Type of research

Randomized and quasi-randomized controlled trials;

Participants

Psoriasis Patients

Interventions

The experimental group for infliximab, the control group for placebo or methotrexate

Outcomes

The efficacy of infliximab therapy was determined according to the patients' Psoriasis Area and Severity Index (PASI) score before and after treatment. The observed Total Efficiency, TE= (cure + markedly effective) /total number of cases × 100%. The adverse events were also observed during treatment.

Exclusion criteria

Have serious heart, liver, kidney and blood system diseases Infliximab allergies

 

Methods

Search strategy

A systematic search of PubMed, Medline, EMBASE and Web of science from 1966 to 2014 using the search terms 'infliximab' and 'psoriasis' were conducted.

An electronic search was conducted in the EMBASE (1974–2014), PubMed(1966–2014) and the Cochrane library 2013.4^th databases. The search was limited to the English language. Key words: infliximab, psoriasis, randomized, controlled.

For the process and method of searching publications, see Figure 1.

Figure 1. The basic selection steps of publications.

Data extraction

Two reviewers independently screened titles and abstracts for potential eligibility. Full text was screened to determine final eligibility. Disagreements were resolved by consultation. Two reviewers re-read the article, analyzed paragraph ambiguity, corrected errors, and reached a consensus, if they made different initial conclusions. Quality analysis was carried out using the method described in Jüni¹⁰ et al. Four quality evaluation criteria were used for the assessment of randomized controlled trials: 1. Did the trial use the correct randomized method? 2. Is concealment of allocation assessed and is the method correct? 3. Was the blind method used in the trial? 4. Does the trial have withdrawals or dropouts? Does the trial have the intention to treat analysis if follow ups or drop outs occur? If all 4 evaluation criteria are met then there is a low risk of bias. However if one or more of the quality evaluation criteria is only partly met then there is a moderate risk of bias. If one or more of the quality evaluation criteria are totally not met then there is a high risk of bias. In addition, we reviewed the literature by the quality criteria of the Jadad scale (see Table 1). 1–2 points were used to indicate low-quality research, while 3–5 points were assigned to high-quality research.

Table 1. Methodology quality assessment-jadad scale

The methods to generate the sequence of randomization.
2 points:	The method to generate the sequence of randomization was described and it was appropriate (table of random numbers, computer generated, etc.)
1 point:	The method of generate the sequence of randomization was stated but not in detail.
0 point:	The method to generate the sequence of randomization was described and it was inappropriate (patients were allocated alternatively, or according to date of birth, hospital number, etc.)
Double blinding
2 points:	The method of double blinding was described and it was appropriate (identical placebo, active placebo, dummy, etc.)
1 point:	The research was described as double blind but the method was not in detail.
0 point:	The research was described as double blind but the method of blinding was inappropriate.
Withdrawal or dropouts
1 point:	The number and the reason for withdrawal in each group were stated in detail.
0 point:	No statement on withdrawals and dropouts.

Allocation concealments of Cochrane systematic review are classified according to the following standards: Grade A: adequate, that considered allocation concealment to be appropriate in the research if centralized randomization, numbered, coded vehicles, or opaque, sealed, and sequentially numbered envelopes were reported; Grade B:unclear, that considered allocation concealment to be unclear in the research if the author did not reported allocation concealments or the reported concealments did not belong in the Grade A category; Grade C: inadequate, that considered concealments were not sufficient or the allocations were not concealed, such as cross-assignment or allocation of record number.

Statistical analysis

The Cochrane collaboration RevMan 5.2 version software was used for meta-analysis. All the outcome measures were categorical data in our systematic review. We therefore took the Odds ratio (OR) and 95%CI for statistical analysis of efficacy. Subgroup analysis was based on heterogeneous factors that may arise. We used the fixed effect mode to summarize each subgroup of similar research for meta-analysis when the research of sub groups have enough similarity (p ≥ 0.1); we used the random effects model to calculate the OR value of total results when there was heterogeneity between subgroups of included research (between subgroups p < 0.05); we used a sensitivity analysis method when heterogeneity was caused by low quality research. Efficacy analysis of the research used the same meta-analysis when there was only one research study in the subgroup.

Results

The general data of included research

The initial search identified 1376 articles. There were 38 articles with controlled clinical trials after exclusion based on repetition, review, basic experiment, and the summary of clinical experimentation. It was found that 13 controlled trial articles met the inclusion standard after a thorough read of the entire articles. Included in the 13 trial articles were 7 articles on psoriasis vulgaris treated by infliximab, 5 articles regarding the treatment of psoriasis arthritis (PsA) by infliximab, and 1 article covering the treatment of palmoplantar psoriasis by infliximab. However, a number of articles were unsuitable for meta-analysi, because the categorical data classified standard is not unified.

The baseline data of the included research

Quality analysis of 13 included research articles (see Table 2).

Table 2. Baseline data of included researches

Research	Methods	Allocation concealment	Participants	Interventions	Outcome measures	Jadad scale
Alan Menter^11	Random Double-blinded	Mentioned A	313 patients in infliximab 3 mg/kg, 314 patients in infliximab 5 mg/kg,208 patients in placebo	10 weeks infliximab 3 or 5 mg/kg and placebo	PASI 75 efficiency	4
Hidesshi Torii^12	Random Double-blinded	Mentioned A	35 patients in infliximab 5 mg/kg, 19 patients in placebo	10 weeks infliximab 5 mg/kg and placebo	PASI 75 efficiency	4
J.Barker^13	Open-label, active-controlled, Random	Mentioned B	653 patients in infliximab 5 mg/kg,, 215 patients in methotrexate	10 weeks infliximab 5 mg/kg and placebo	PASI 75 efficiency	2
Kristian Reich^14	Random Double-blinded	A	301 patients in infliximab 5 mg/kg, 77 patients in placebo	10 weeks infliximab 5 mg/kg and placebo	PASI 75 efficiency	4
S.R.Feldman^15	Random Double-blinded	A	99 patients in infliximab 3 mg/kg, 99 patients in infliximab 5 mg/kg, 51 patients in placebo	10 weeks infliximab 3 or 5 mg/kg and placebo	PASI 75 efficiency	4
U Chaudhari^16	Random	B	11 patients in infliximab 5 mg/kg, 11 patients in placebo	10 weeks infliximab 5 mg/kg and placebo	PASI 75 efficiency	2
YANG.Hai-zhen^17	Random Double-blinded	A	84 patients in infliximab 5 mg/kg, 45 patients in placebo	10 weeks infliximab 5 mg/kg and placebo	PASI 75 efficiency	4
A Karanaugh^18	Random Double-blinded	A	100 patients in infliximab 5 mg/kg, 100 patients in placebo	24 weeks infliximab 5 mg/kg and placebo	ACR 20 efficiency	4
Antoni C^19	Random Double-blinded	A	100 patients in infliximab 5 mg/kg, 100 patients in placebo	14 weeks infliximab 5 mg/kg and placebo	ACR 20 efficiency	4
Asta Baranauskaite^20	Open-label, Random	B	51 patients in infliximab+ methotrexate 5 mg/kg, 48 patients in methotrexate	16 weeks infliximab 5 mg/kg and placebo	ACR 20 efficiency	2
Christian E. Antoni^21	Random Double-blinded	A	52 patients in infliximab 5 mg/kg, 52 patients in placebo	16 weeks infliximab 5 mg/kg and placebo	ACR 20 efficiency	4
LAURAC COATES^22	Random Double-blinded	A	31 patients in infliximab 5 mg/kg, 32 patients in placebo	16 weeks infliximab 5 mg/kg and placebo	ACR 20 efficiency	4
R.Bissonnette^23	Random Double-blinded	A	12 patients in infliximab 5 mg/kg, 12 patients in placebo	14 weeks infliximab 5 mg/kg and placebo	m-PPPASI efficiency	4

Results of meta-analysis

The efficacy of infliximab and placebo in the controlled treatment of psoriasis vulgaris

The efficacy of infliximab (5mg/kg) and placebo in the controlled treatment of psoriasis vulgaris

The 7 research studies had both clinical and statistical homogeneity (χ² = 49.76, p < 0.00001).The meta-analysis results showed that statistically significant differences in efficacy were found for the infliximab (5 mg/kg) group compared with control group which received placebo in treatment of psoriasis vulgaris[OR 13.55, 95%CI (11.14,16.48)]^11-17 (see Fig. 2).

Figure 2. The meta-analysis result of infliximab (5 mg/kg) group in treatment of psoriasis vulgaris in efficacy.

The efficacy of infliximab (3mg/kg) and placebo in controlled treatment of psoriasis vulgaris

Two research papers had clinical homogeneity and statistical homogeneity(χ² = 1.81, p  =  0.18).The results of meta-analysis showed that statistically significant differences in efficacy were found between the infliximab (3 mg/kg) group compared with control group that received placebo in treatment of psoriasis vulgaris. [OR85.45, 95% CI (39.13, 186.58)]^11,15 (see Fig. 3).

Figure 3. The meta-analysis result of infliximab (3 mg/kg) group in treatment of psoriasis vulgaris in efficacy.

For statistical results, see Table 3.

Table 3. The meta-analysis result (grouped by the dose of infliximab)

			Heterogeneity Test			Total effective rate
Outcome	Number of reference	N	χ^2	p	Model	OR	95%CI	Z	p
Inf5mg/kg	7	1497	49.76	0.00001	Fixed	13.55	(11.14,16.48)	26.05	<0.0001
Inf3mg/kg	2	412	1.81	0.18	Fixed	85.45	(39.13,186.58)	11.16	<0.0001

The efficacy of infliximab (5mg/kg) and placebo in the controlled treatment of psoriasis arthritis (PsA)

The 5 research studies had clinical homogeneity and statistical homogeneity (χ²=8.28, p=0.08).The results of meta-analysis showed that statistically significant differences in efficacy were found for the infliximab (5 mg/kg) group compared with the control group, which received placebo in treatment of psoriasis arthritis(PsA) [OR8.36, 95% CI (5.63, 12.40)]^18-22 (see Fig. 4).

Figure 4. The meta-analysis result of infliximab (5 mg/kg) group in treatment of psoriasis arthritis (PsA) in efficacy.

The efficacy of infliximab (5mg/kg) and placebo in controlled treatment of palmoplantar psoriasis

One controlled trial used infliximab (5 mg/kg) for the treatment of palmoplantar psoriasis. Twenty-four patients were randomized (1:1) to receive either infliximab 5 mg/kg or placebo. At week 14, 33.3% (4 of 12) of patients randomized to receive infliximab reached m-PPPASI 75 compared to 8.3% (1 of 12) on placebo.²¹

Adverse events

The occurrence of adverse events during infliximab treatment was reported in 13 articles. These adverse events included: pain, headache, nausea, diarrhea, vomiting, infusion reactions, abnormal liver function tests, development of antinuclear antibodies, nasopharyngitis, malaise, leucopenia, pruritus, musculoskeletal pain, allergic reaction, lymphoproliferative disorders, and the development of malignancies. Pain, abnormal liver function tests, and infusion reactions are more common adverse effects associated with infliximab treatment.

For statistical results, see Table 4.

Table 4. The incidence rates of adverse events during infliximab treatment

Adverse events	No. of patients with adverse events	Incidence rates (total 1816 patients from 9 articles)
Pain	128	7.05%
Headache	48	2.64%
Nausea	11	0.61%
Diarrhea	10	0.55%
Vomiting	2	0.11%
Infusion reactions	195	10.74%
Abnormal liver function tests	53	2.92%
Development of antinuclear antibodies	20	1.10%
Nasopharyngitis	43	2.37%
Malaise	32	1.76%
Leucopenia	2	0.11%
Pruritus	42	2.31%
Musculoskeletal pain	2	0.11%
Allergic reaction	6	0.33%
Lymphoproliferative disorders and Development of malignancies	1	0.06%

Discussion

Study quality

This meta-analysis investigated the efficacy as well as the adverse effects of infliximab in the treatment of patients with psoriasis. The use of evidence-based medicine to study the published articles provides the best clinical evidence for use of infliximab in the treatment of psoriasis. A number of articles can be retrieved by querying domestic and foreign websites. Unfortunately, few articles meet the standards of meta-analysis and can be combined due to the outcome measures used in the statistical methods employed in this study. Meta-analysis of the infliximab clinical trials found that 13 controlled trial articles met the inclusion standard. The analysis results included 7 articles on the treatment of psoriasis vulgaris by infliximab, 5 articles regarding psoriasis arthritis (PsA) treated by infliximab, and one article on the treatment of palmoplantar psoriasis by infliximab. Eleven out of 13 articles were randomized controlled trials and these were considered as high quality reports. Only 2 low quality articles were non-blinded randomized trials.

Efficacy

Our systematic review confirms that infliximab is effective in the treatment of psoriasis vulgaris, psoriasis arthritis, and palmoplantar psoriasis. The results of our literature meta-analysis show that statistically significant differences in efficacy were found for the infliximab (5 mg/kg) group compared with the control group which received placebo during treatment of psoriasis vulgaris [OR 13.55, 95% CI (11.14, 16.48). Statistically significant differences in efficacy were found for the infliximab (3 mg/kg) group in the treatment of psoriasis vulgaris as compared with the control group which received placebo [OR 85.45, 95% CI (39.13, 186.58)]. There were also significant differences in the efficacy between infliximab (5 mg/kg) treated group and the placebo control group when administered to patients with psoriasis arthritis (PsA) [OR 8.36, 95% CI (5.63, 12.40)]. One research report examined the use of 5mg/kg infliximab in the treatment of palmoplantar psoriasis in a controlled clinical trial. Twenty-four patients were randomized (1:1) to receive infliximab 5 mg/kg or placebo. At week 14, 33.3% (4 of 12) of patients randomized to infliximab reached m-PPPASI 75 as compared to only 8.3% (1 of 12) on placebo.

In adults, infliximab can be administered at a single dose of 3 mg/kg, 5kg/kg or 10mg/kg, with repeated infusions at 2 and 6 weeks. Continued repeated treatment can be applied at 14 and 22 weeks depending on the disease. According to the observations made in our searched articles, the effects of the drug on patient's condition can last up to 1 y.

Safety

The main cause of withdrawal or dropouts in the infliximab studies was due to the occurrence of adverse events. The most common drug-induced adverse events associated with infliximab were pain, hepatic dysfunction and infusion reaction. These symptoms were subsequently followed by secondary infections such as hepatitis and fungal disease.

Implications for future research

First, the studies contained a relatively small sample size. Therefore the results need to be further validated and confirmed. However, the high quality of studies on other populations such as Asian populations improves the credibility of our results. Second, the baseline of the severity of the disease and the prevalence of patients with other comorbidities were diverse, which could also limit the accuracy of this meta-analysis.

Infliximab is a new therapeutic agent for the treatment of severe psoriasis. The expensive price and adverse events associated with infliximab are limiting the widespread application of this drug in the clinic. In the future, we hope that a thorough large scale clinical trial of infliximab on patients with psoriasis will provide valuable data on the long-term efficacy and recurrence.

In conclusion, infliximab treatment is well tolerated and leads to significant associated with symptom relief in psoriasis patients. More clinical trials and economic studies are needed to establish infliximab as a front line treatment for psoriasis.

Disclosure of Potential Conflicts of Interest

The authors do not have any conflicts of interest on this paper.

Author Contributions

L.T.Z and J.W. designed the project, supervised experiments. J.W, and Q.X.Z collected and analyzed the data. J.W. and L.T.Z wrote the manuscript. Other authors performed data analysis and revised the manuscript.

Acknowledgments

We thank Dr. Ying Li (Peking University Health Science Center (PUHSC)) for critical reading of this manuscript and preparing the manuscript.

Funding

Funding was supported by Tianjin Natural Science Foundation, grant no. 12JCYBJC17200.